Abstract
Nitric oxide (NO), a vasodilator involved in the regulation of pulmonary vascular tone, is synthesized by a family of enzymes, nitric oxide synthases (NOS). To investigate whether adenoviral-mediated overexpression of constitutive endothelial NOS (ceNOS) would attenuate hypoxic pulmonary vasoconstriction, we aerosolized 3 x 109 plaque forming units of a recombinant adenovirus containing the ceNOS gene (AdCMVceNOS) into rat lungs. Four days after infection, transgene expression was confirmed using immunoblot techniques. Diffuse ceNOS immunostaining was detected in alveoli and medium-sized and small pulmonary vessels of AdCMVceNOS-transduced lungs. AdCMVceNOS-transduction was associated with an 86% increase in [3H]arginine to [3H]citrulline conversion and a rise in pulmonary cGMP levels from 7±1 to 59±9 pmol/mg protein in lungs from AdCMVceNOS versus control rats, (P < 0.05). During acute hypoxia (FIO2 = 0.10) for 25 min, mean pulmonary artery pressure (PAP) increased significantly from 17±1 to 27±1 mmHg in rats aerosolized with saline (n = 4) and from 18±1 to 28±1 mmHg in rats given an adenoviral vector expressing a nuclear-targeted β-galactosidase gene (AdCMVβgal, n = 8). In contrast, in AdCMVceNOS-transduced rats (n = 8) the hypoxia-induced increase in PAP was significantly attenuated (18±1 to 23±2 mmHg). Systemic blood pressure was not affected by aerosol gene transfer. Thus, adenoviral-mediated ceNOS gene transfer to rat lungs increases ceNOS expression and activity, and reduces acute hypoxic pulmonary vasoconstriction. Aerosolized recombinant adenovirus overexpressing vasodilatory proteins can act as a selective pulmonary vasodilator and may hold promise as a future therapeutic strategy for pulmonary hypertension.
Original language | English (US) |
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Pages (from-to) | 317-324 |
Number of pages | 8 |
Journal | Journal of Clinical Investigation |
Volume | 98 |
Issue number | 2 |
DOIs | |
State | Published - Jul 15 1996 |
Keywords
- adenovirus
- gene therapy
- guanylate cyclase
- hypoxia
- pulmonary hypertension
ASJC Scopus subject areas
- General Medicine